Method for the synthesis of amines and amino acids with organoboron derivatives

ABSTRACT

Amines and amino acids are prepared by reacting an amine, a carbonyl derivative, and an organoboron compound under mild conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is based on and claims the benefit under 35 U.S.C. §119(e) of U.S. provisional application serial No. 60/020,741, filed Jun.28, 1996, incorporated herein by reference in full.

FIELD OF THE INVENTION

This invention relates to the fields of organic synthesis, organoboronchemistry, medicinal chemistry and combinatorial chemistry. Morespecifically, the invention relates to methods for preparing amines andamino acids using organoboron compounds.

BACKGROUND OF THE INVENTION

A variety of amines and amino acids (1-8) are of particular interest forthe preparation of many types of compounds that are of interest tochemical, agrochemical, biotechnology and pharmaceutical industries. Inparticular there is a need for a method which allows the production ofnovel combinatorial libraries of amines and amino acids and is alsosuitable for the large scale preparation of such compounds.

α-Amino acids (3) constitute a major class of naturally occurringmolecules and have important and diverse biological functions. (G. C.Barrett, Ed., “Chemistry and Biochemistry of the Amino Acids”, Chapmanand Hall, London, (1985)). Nearly a thousand naturally occurring aminoacids are known and their number is constantly increasing. Besides theirprofound biological role as constituents of proteins, amino acids havebeen extensively used in organic synthesis as convenient and versatileprecursors to many other target molecules.

Although there are many known methods for the synthesis of amino acids(R. M. Williams, “Synthesis of Optically Active α-Amino Acids”, PergamonPress, Oxford, (1989); R. M. Williams, Aldrichim. Acta (1992) 25:11; R.O. Duthaler, Tetrahedron (1994) 50:1539), most of these have a number ofdrawbacks including the use of toxic or hazardous reagents, the need foranhydrous or anaerobic conditions, the cumbersome isolation procedures,the requirement for multiple reaction steps, the limited applicabilityto certain substitution patterns, and difficulty in controlingstereochemistry or isomeric purity.

In addition to the need to develop practical synthetic routes to thenatural amino acids, for which there is a large and growing market,there is also an increasing demand for new methods to prepare diversenon-natural derivatives. Such compounds can serve as building blocks incombinatorial peptide synthesis and for the development of enzymeinhibitors, peptidomimetics and other bioactive molecules (G. M. Coppolaand H. F. Schuster, “Asymmetric Synthesis: Construction of ChiralMolecules Using Amino Acids”, Wiley-Interscience, New York, (1987)).Amino acids with unusual side chains or with conformationally restrictedbackbones are of great interest due to their potential ability forhighly selective receptor binding.

The valuable role of amines and amino acids in a variety of commercialapplications requires practical and efficient methods for theirpreparation. This type of synthetic technology should have two importantfeatures, both of which are characteristic of the present invention: Atthe research and development stage, it is highly desirable to employmethods that allow the rapid production of a diverse array of moleculeshaving many types of structural modifications, allowing the facilepreparation of combinatorial libraries. Also, once a commercial productis identified, the required methodology for its large scale preparationshould be characterized by high efficiency, low cost, facile isolationand purification, and low environmental hazards.

Known methods of multicomponent synthesis include the Strecker aminoacid synthesis which involves the addition of cyanide to the adduct of acarbonyl compound and an amine to form aminonitriles, which can behydrolyzed to amino acids. Another related method is the Ugimulticomponent reaction (I. Ugi et al. Endeavour (1994) 18:115), whichinvolves the use of isonitriles for the formation of adducts which canbe hydrolyzed to peptide derivatives.

The use of organoboron derivatives for the synthesis of substitutedamines and amino acids in a multicomponent fashion as described herein,has no precedent in the literature. Although I have previously reportedpreliminary results on the use of (E)-alkenyl boronic acids for thesynthesis of (E)-allylamines from amines and paraformaldehyde (N. A.Petasis et al., Tetrahedron Lett. (1993) 34:583), this initial stepwiseprocedure involves high temperatures and rather harsh conditions whichare quite limited in scope due to the decomposition of the startingmaterials and intermediates. Thus, while the reported method can be usedfor the preparation of simple allylamines, it is not suitable for thesynthesis of more substituted allylamines or amino acids, which have tobe derived from aldehydes and ketones other than paraformaldehyde, orfrom other types of boronic acids.

From the mechanistic point of view, the chemistry covered by thisinvention resembles a boron-directed Mannich reaction. While theconventional Mannich reaction is known (E. F. Kleinman et al.,Comprehensive Organic Synthesis (1991) 4:893; H. Heaney, ComprehensiveOrganic Synthesis (1991) 4:953; M. Tramontini and L. Angiolini, “MannichBases: Chemistry and Uses”, CRC Press, Boca Raton, (1994)), the use ofrelatively stable organoboron compounds to deliver various organicgroups in a directed and stereocontrolled manner is not reported. Theonly types of boron-based reagents that are known to add to imines arethe highly reactive allylic boranes and allylic boronates (W. R. Roush,Comprehensive Organic Synthesis (1991) 2:1; E. F. Kleinman et al.,Comprehensive Organic Synthesis (1991) 4:975; Y. Yamamoto et al., Chem.Rev. (1993) 93:2207). However, despite an apparent similarity amongallylic organoboron compounds with the corresponding alkenyl, aryl oralkyl derivatives, there is a significant difference in theirreactivity. Thus, the “Grignard-like” addition of allylic nucleophilesto carbonyl-derived electrophiles involves a cyclic six-memberedtransition state. This mode of action, however, is not possible withother organoboron compounds, such as the ones utilized herein.

Among the compounds of interest are β,γ-unsaturated-α-amino acids (3, R³or R⁴=alkenyl), which have found numerous applications as syntheticintermediates and as mechanism-based suicide enzyme inhibitors,particularly of enzymes that metabolize amino acids, such asdecarboxylases, transaminases or aminotransferases (L. Havlicek et al.,Collect. Czech. Chem. Commun. (1991) 56:1365).

Another important class of amino acids is the aryl glycines (3, R³ orR⁴=aryl), which is found in many glycoptide and β-lactam antibiotics (R.M. Williams et al., Chem. Rev. (1992) 92:889). The synthesis of suchamino acids by other methods is often hampered by their facileepimerization and the difficulty to control stereochemistry andisomerism.

N-carboxymethyl amino acid or peptide derivatives, i.e. compounds of thegeneral formula 5, are especially valuable as peptidomimetics and havebeen used in several enzyme inhibitors (C. J. Blankley et al., J. Med.Chem. (1987) 30:992; J. Krapcho et al., J. Med. Chem. (1988) 31:1148).Among the most notable is enalaprilat 9 (the active ingredient in thedrug vasotec) and lisinopril (10), which are potent inhibitors ofangiotensin-converting enzyme (ACE) used clinically for the treatment ofhypertension (I. M. Wilde et al., Pharmaeconomics (1994) 6:155). Similarcompounds have also been considered as inhibitors of metalloproteinases(K. Chapman et al., J. Med. Chem. (1993) 36:4293) with a potential useagainst cancer, arthritis and other diseases.

Other compounds of ineterest include substituted amines (1) andparticularly allylic or benzylic amines (2), 1,2-diamines (6), 1,2-aminoalcohols (7) and α-amino aldehyde derivatives (8), all of which are verycommon components of a variety of bioactive molecules, includinginhibitors of proteases and other enzymes, which are used aspharmaceuticals or agrochemicals. Among the compounds of the generalformula 8 are those having additional hydroxyl groups within R⁴ or R⁸which include various amino sugar derivatives (R. W. Jeanloz, “The AminoSugars”, Academic Press, New York, (1969) exemplified by 11 and 12.

SUMMARY OF THE INVENTION

I have now invented a practical and effective method for the synthesisof various amines and amino acids by combining certain organoboronderivatives, including organoboronic acids, organoboronates andorganoborates with primary or secondary amines and carbonyl compounds.This process constitutes a 3-component reaction and is suitable for therapid generation of combinatorial libraries of amines, amino acids andpeptidomimetic components.

The synthetic procedure is quite simple and works in a variety ofsolvents, including water, ethanol, dichloromethane and toluene. Productisolation is also very simple and can give fairly pure products withoutthe need for chromatography or distillation. Of special significance isthe fact that this process generates new C—C bonds with very highstereoselectivity (up to more than 99% de and 99% ee) when certainchiral components are used in the reaction. Due to its operationalsimplicity and the fact that no hazardous chemicals or specialprecautions are required, this invention is suitable for the practicaland convenient synthesis of many types of amines and amino acids,including stereochemically pure derivatives. In this manner, thisinvention is useful for the preparation of various pharmaceuticals andagrochemicals.

One aspect of the invention is a process for generating substitutedamines and amino acids, by reacting an organoboron compound with acarbonyl derivative and an amine under mild conditions.

Another aspect of the invention is a process for generating acombinatorial library of amines, amino acids, or amino acid mimics, byreacting an organoboron compound with a carbonyl derivative and an amineunder mild conditions.

Another aspect of the invention is a combinatorial library generatedthrough the process of the invention. The invention offers uniqueopportunities for the one-step introduction of a diverse group offunctional groups in a variety of locations on the molecules produced,located in up to 8 substituent groups.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Definitions:

An organoboron derivative, as defined herein, comprises a compoundhaving a boron atom connected to at least one alkyl, alkenyl, aryl,allenyl or alkynyl group.

Alkyl groups of the present invention include straight-chained, branchedand cyclic alkyl radicals containing up to about 20 carbons. Suitablealkyl groups may be saturated or unsaturated. Further, an alkyl may alsobe substituted one or more times on one or more carbons withsubstituents selected from the group consisting of C1-C6 alkyl, C3-C6heterocycle, aryl, halo, hydroxy, amino, alkoxy and sulfonyl.Additionally, an alkyl group may contain up to 10 heteroatoms. Suitableheteroatoms include nitrogen, oxygen and sulfur.

Aryl groups of the present invention include aryl radicals which maycontain up to 10 heteroatoms. An aryl group may also be optionallysubstituted one or more times with an aryl group or a lower alkyl groupand it may be also fused to other aryl or cycloalkyl rings. Suitablearyl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl,pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.

The term “combinatorial library” as used herein refers to a set ofcompounds that are made by the same process, by varying one or more ofthe reagents. Combinatorial libraries may be made as mixtures ofcompounds, or as individual pure compounds, generally depending on themethods used for identifying active compounds. Where the active compoundmay be easily identified and distinguished from other compounds presentby physical and/or chemical characteristics, it may be preferred toprovide the library as a large mixture of compounds. Large combinatoriallibraries may also be prepared by massively parallel synthesis ofindividual compounds, in which case compounds are typically identifiedby their position within an array. Intermediate between these twostrategies is “deconvolution”, in which the library is prepared as a setof sub-pools, each having a known element and a random element. Forexample, using the process of the invention each sub-pool might beprepared from only a single amine (where each sub-pool contains adifferent amine), but a mixture of different carbonyl derivatives (ororganoboron reagents). When a sub-pool is identified as having activity,it is resynthesized as a set of individual compounds (each compoundhaving been present in the original active sub-pool), and tested againto identify the compounds responsible for the activity of the sub-pool.

General Description:

This invention involves the use of organoboron compounds in a C—C bondforming reaction where the electrophile is derived from a carbonyl andan amine and the product is a new substituted amine or amino acid. Thereare several variations of this methodology involving differentorganoboron, carbonyl and amine components:

Synthesis of amines: One aspect of the invention is a process forgenerating a combinatorial library consisting of compounds of formula 1,by combining compounds 13, 14 and 15:

where R¹ and R² are each independently selected from the groupconsisting of alkyl, hydrogen, cycloalkyl, aryl, heteroaryl, acyl,carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,triarylsilyl, phosphinyl, and —YR, where Y is selected from the groupconsisting of —O—, —NR_(a)—, —S—, —SO—, and —SO₂—, and R and R_(a) areeach independently selected from the group consisting of hydrogen,alkyl, aryl, heteroaryl, and acyl, or R¹ and R² together form amethylene bridge of 2 to 20 carbon atoms; and where R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl, and heteroaryl; and where R⁵ isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, alkenyl, alkynyl and allenyl; R⁶, R⁷ are selected from thegroup consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro,bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino,acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl,cycloalkyl, aryl, and heteroaryl, or together form a methylene bridge of3 to 7 atoms.

Following their formation, the products of the invention (1) can besubsequently easily transformed to new derivatives. For example,removing groups R¹ and R² can provide primary amines, while joining twoor more groups will result in the formation of cyclic or polycyclicamines.

The multicomponent nature of the process described in this inventionallows the direct and rapid generation of combinatorial libraries of theproducts, by varying the desired substituents. Such libraries can begenerated either in solution or in the solid phase, upon attachment ofone substituent onto a solid support. For example, one may couple theamine component (13) to a substrate through either R¹ or R², and reactthe immobilized amine to a mixture of different organoboron compounds(15, where R⁵ is a variety of different groups) and individual or mixedcarbonyl compounds (14) to produce a mixture of bound products (1).Alternatively, the carbonyl compound may be immobilized, and a mixtureof organoboron compounds and diverse amines added. Combinatoriallibraries may be generated either as individual compounds or as mixturesof compounds.

In another embodiment of the invention an organoboron compound (19) iscombined with a preformed iminium derivative (16), aminol (17), oraminal (18), prepared by the combination of an amine (13) and a carbonylcompound (14), or by other methods:

where R⁵ is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl, alkenyl, alkynyl and allenyl; R⁶, R⁷ and R⁸ areselected from the group consisting of hydroxy, alkoxy, aryloxy,heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form amethylene bridge of 3 to 7 atoms; X is a positive counter ion, and n is0 or 1. Such reactions can take place directly or upon the addition of aLewis acid. In the case of fluoroborates (19, R⁶═R⁷═R⁸═F) the reactionmay be promoted by the addition of a silyl derivative SiR⁹R¹⁰R¹¹R¹²,where R⁹ is selected from the groups consisting of: chloro, bromo, iodo,alcoxy, acyloxy, triflate, alkylsulfonate or arylsulfonate, whilesubstituents R¹⁰, R¹¹ and R¹² are selected from the groups consistingof: alkyl, cycloalkyl, aryl, alkoxy, aryloxy or chloro. A preferred R⁵is an alkenyl or aryl group leading to the formation of geometricallyand isomerically pure allylamines or benzylamines (2), respectively.

Synthesis of α-amino acid derivatives: This invention can be employeddirectly for the synthesis of α-amino acids (3) by combining anorganoboron compound (21) with an amine (13) and an α-keto acid (20).

The reaction can proceed directly in a variety of solvents, includingwater, alcohols, ethers, hydrocarbons, chlorinated hydrocarbons andacetonitrile. It can also be promoted by adding Lewis acids, such ascompounds containing electron-deficient atoms including boron,lanthanum, silicon, tin, titanium and zinc.

The stereochemistry of the product in these reactions can be controlledby the use of a chiral amine, a chiral carbonyl compound or a chiralorganoboron derivative (L. Deloux et al., Chem. Rev. (1993) 93:763). Theuse of chiral amines or similar amino alcohol or amino acid derivativescan give products with a high degree of diastereocontrol (up to 99.5%de). Removal of the chiral group substituent can give the free aminoacid with a high enantiomeric excess (up to 99.5% ee).

The types of organoboron compounds that can be used in this mannerinclude compounds 21 that have R⁴ selected from the group consisting ofalkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl,including substituted and isomerically pure derivatives. The boronsubstituents R⁵ and R⁶ which do not appear in the product 3, areselected from the groups consisting of: hydroxy, alkoxy, aryloxy,heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted andisomerically pure derivatives. Groups R⁵ and R⁶ may be connectedtogether to form a bridge of 3 to 7 atoms. Substituents R³ in compound20 are selected from the group consisting of hydrogen, carboxy, alkyl,cycloalkyl, aryl, hetero aryl, including substituted and isomericallypure derivatives. Substituents R¹ and R² in amine 13 are selected fromthe groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, alkylthio, arylthio, acylthio,trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl,phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted andisomerically pure derivatives. Groups R¹ and R² may be connectedtogether to form a bridge of 2 to 20 atoms.

The reactants are combined in approximately equimolar amounts in thesolvent, and maintained at a temperature between about 0° C. and thereflux temperature of the solvent, preferably between about 25° C. andabout 65° C., until the reaction is complete. The course of the reactionmay be followed by any standard method, including thin-layerchromatography, GC and HPLC. In general, the reaction is conducted forabout 1 to about 72 hours, preferably about 12 to about 24 hours.Product isolation usually gives fairly pure products without the needfor chromatography or distillation.

The products 3 of the invention can be subsequently transformed toproduce new derivatives. For example, removing groups R¹ and R² canprovide primary amino acids, while joining two or more groups willresult in the formation of cyclic or polycyclic derivatives. A number ofamine components (13) can be used which include R¹ and R² groups thatcan be easily removed in subsequent reactions. For example, benzylaminederivatives can be cleaved by hydrogenation, while others, such as thedi(p-anisyl)methylamino group or the trityl group, can be removed underacidic conditions which prevent facile racemization.

The multicomponent nature of the process described in this inventionallows the direct and rapid generation of combinatorial libraries of theproducts, by varying the desired substituents. Such libraries can begenerated either in solution or in the solid phase, upon attachment ofone substituent onto a solid support. For example, one may couple anamine (13) to a substrate through either R¹ or R², and react theimmobilized amine with a mixture of different organoboron compounds(21), where R⁴ is a variety of different groups) and individual or mixeddicarbonyl compounds (20) to produce a mixture of bound products (3).Alternatively, the dicarbonyl compound may be immobilized, and a mixtureof organoboron compounds and diverse amines added. Combinatoriallibraries may be generated either as individual compounds or as mixturesof compounds.

The present invention is particularly suitable for the synthesis ofβ,γ-unsaturated-α-amino acids and their derivatives. The requiredalkenyl boronic acids or boronates (22) can be easily and convenientlyprepared from alkynes (A. Suzuki, Top. Curr. Chem. (1983) 112:67; E.Negishi et al., Org. React. (1985) 33:1; D. S. Matteson, Chemistry ofthe Metal Carbon Bond (1987) 4:307; A. Pelter et al., “Borane Reagents”,Academic Press, London, (1988); K. Smith et al., Comprehensive OrganicSynthesis (1991) 8:703; N. Miyaura et al., Chem. Rev. (1995) 95:2457).

Indeed, reaction of an alkenyl boronic acid or boronate with a mixtureof an α-keto acid derivative (such as glyoxylic acid or pyruvic acid)and a primary or secondary amine, gives the corresponding amino acids inhigh yields. The reaction works in a variety of solvents, includingwater, ethanol, toluene and dichloromethane. Product isolation isusually straight forward, since the product generally precipitates outand can be isolated by filtration.

Substituents R¹ and R² in the amine component 13 are selected from thegroup consisting of hydrogen alkyl, cycloalkyl, aryl, hetero aryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio,acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, includingsubstituted and isomerically pure derivatives. Groups R¹ and R² may beconnected together to form a bridge of 2 to 20 atoms. Substituents R³ incompound 20 are selected from the group consisting of hydrogen, carboxy,alkyl, cycloalkyl, aryl, hetero aryl, including substituted andisomerically pure derivatives. Groups R⁵, R⁶ and R⁷ in compound 22 areselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, allenyl, alkoxy, aryloxy, heteroaryloxy,chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino,acylamino, carboxamido, thio, alkylthio, arylthio and acylthio,includingsubstituted and isomerically pure derivatives. The boron substituents R⁸and R⁹ which do not appear in the products, are selected from the groupconsisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo,fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino,carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl,aryl and heteroaryl, including substituted and isomerically purederivatives. Groups R⁸ and R⁹ may be connected together to form a bridgeof 3 to 7 atoms.

The use of other α-dicarbonyl compounds (23) leads to more substitutedderivatives (4).

Groups R¹ and R² in the amine component 13 are selected from the groupconsisting of hydrogen alkyl, cycloalkyl, aryl, hetero aryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio,trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl,phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted andisomerically pure derivatives. Groups R¹ and R² may be connectedtogether to form a bridge of 2 to 20 atoms. Substituents R³ and R⁴ incompound 24 are each independently selected from the group consisting ofhydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio,arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl. The boronsubstitutent R⁵ in compound 15 is selected from the group consisting ofalkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl. Theboron substituents R⁶ and R⁷ which do not appear in the products, areselected from the group consisting of hydroxy, alkoxy, aryloxy,heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including substitutedand isomerically pure derivatives. Groups R⁶ and R⁷ may be connectedtogether to form a bridge of 3 to 7 atoms.

Synthesis of N-carboxymethyl amino acid derivatives: The use of α-aminoacid derivatives (25) as the amine components in this process, leads toN-carboxymethyl amino acid products (5) with a very high degree ofdiastereocontrol.

Substituents R¹ and R² in the amino acid component 25 are selected fromthe group consisting of hydrogen alkyl, cycloalkyl, aryl, hetero aryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio,acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, includingsubstituted and isomerically pure derivatives. Groups R¹ and R² may beconnected together to form a bridge of 2 to 20 atoms. Groups R⁸ and R⁹are selected from the group consisting of alkyl, cycloalkyl, aryl,hetero aryl, acyl and carboxy,including substituted and isomericallypure derivatives. Groups R⁸ and R⁹ may be connected together or withother groups in 25, 24, or 15 to form a bridge of 3 to 7 atoms.Substituents R³ and R⁴ in compound 24 are each independently selectedfrom the group consisting of hydrogen, hydroxy, alkoxy, aryloxy,heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino,carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl,aryl, and heteroaryl. The boron substitutent R⁵ in 15 is selected fromthe group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl,alkynyl and allenyl. The boron substituents R⁶ and R⁷ which do notappear in the products, are selected from the group consisting ofhydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo,carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio,alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl,including substituted and isomerically pure derivatives.

In another preferred empodiment of the invention, the reaction of aminoacids or peptides(26) with dicarbonyl compounds (20) and alkenyl boronderivatives (22) gives adducts (27) which can be subsequentlyhydrogenated to form the ACE inhibitors (9) and (10), as well as otherrelated compounds.

Substituents R¹ and R² in the amino acid component 26 are selected fromthe group consisting of hydrogen alkyl, cycloalkyl, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio,acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, includingsubstituted and isomerically pure derivatives. Groups R¹ and R² may beconnected together to form a bridge of 2 to 20 atoms. Group R⁴ isselected from the groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl, acyl and carboxy,including substituted and isomerically purederivatives. Groups R⁴ may be connected together or with other groups in26, 20, or 22 to form a bridge of 3 to 7 atoms. Group R³ in compound 20is selected from the group consisting of hydrogen, alkyl, cycloalkyl,aryl, and heteroaryl. Groups R⁵, R⁶ and R⁷ in compound 22 are selectedfrom the groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl,alkenyl, alkynyl, allenyl, alkoxy, aryloxy, heteroaryloxy, chloro,bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino,acylamino, carboxamido, thio, alkylthio, arylthio, acylthio,includingsubstituted and isomerically pure derivatives. The boron substituents R⁸and R⁹ which do not appear in the products, are selected from the groupconsisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo,fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino,carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl,aryl and heteroaryl, including substituted and isomerically purederivatives. Groups R⁸ and R⁹ may be connected together to form a bridgeof 3 to 7 atoms.

Synthesis of 1,2-diamines and 1,2-amino alcohols: In another empodimentof the invention an amine (13) and an organoboron compound are reactedwith carbonyl derivatives of the general formula 28 to give products 29.

Groups R¹ and R² in the amine component 13 are selected from the groupsconsisting of: hydrogen alkyl, cycloalkyl, aryl, hetero aryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio,trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl,phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted andisomerically pure derivatives. Groups R¹ and R² may be connectedtogether to form a bridge of 2 to 20 atoms. Groups R³ in compound 28 areselected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl,and heteroaryl. Groups R⁴ in compound 28 have at least one carbon atomand are attached to a group XH, where X is selected from a groupconsisting of —O—, -—R_(a)—, —S—, and R_(a) is independently selectedfrom the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl,hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino,dialkylamino, and acylamino. The boron substitutent R⁵ in compound 15 isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents R⁶ andR⁷ which do not appear in the products, are selected from the groupsconsisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo,fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino,carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl,aryl, heteroaryl, including substituted and isomerically purederivatives. Groups R⁶ and R⁷ may be connected together to form a bridgeof 3 to 7 atoms.

In one empodiment of the invention an amine (13) and an organoborncompound are reacted with α-amino carbonyl derivatives (30) to give1,2-diamines (6).

Groups R¹ and R² in the amine component 13 are selected from the groupsconsisting of: hydrogen alkyl, cycloalkyl, aryl, hetero aryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio,trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl,phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted andisomerically pure derivatives. Groups R¹ and R² may be connectedtogether to form a bridge of 2 to 20 atoms. Groups R³, R⁴ and R⁸ incompound 30 are selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, and heteroaryl. Groups R⁹ and R¹⁰ in compound 30 areselected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio,acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, includingsubstituted and isomerically pure derivatives. Groups R⁹ and R¹⁰ may beconnected with other groups in compounds 13, 30 or 15 to form a bridgeof 2 to 20 atoms. The boron substitutent R⁵ in compound 15 is selectedfrom the group consisting of alkyl, cycloalkyl, aryl, heteroaryl,alkenyl, alkynyl and allenyl. The boron substituents R⁶ and R⁷ which donot appear in the products, are selected from the group consisting ofhydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo,carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio,alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl,including substituted and isomerically pure derivatives. Groups R⁶ andR⁷ may be connected together to form a bridge of 3 to 7 atoms.

The products 6 of the invention can be subsequently transformed toproduce new derivatives. For example, removing groups R¹ and R² canprovide primary amines, while joining two or more groups will result inthe formation of cyclic or polycyclic derivatives. A number of aminecomponents (13) can be used which include R¹ and R² groups that can beeasily removed in subsequent reactions. For example, benzylaminederivatives can be cleaved by hydrogenation, while others, such as thedi(p-anisyl)methylamino group or the trityl group, can be removed underacidic conditions which prevent facile racemization.

In another empodiment of the invention an amine (13) and an organoboroncompound are reacted with an α-hydroxy carbonyl derivative (31) to give1,2-amino alcohols (7). Compounds 31 can also exist in a hemiacetalform, and can include carbohydrate derivatives. The use of chiralderivatives 31 forms products 7 with a very high degree ofdiastereocontrol (up to 99.5% de).

Groups R¹ and R² in the amine component 13 are selected from the groupconsisting of hydrogen alkyl, cycloalkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio,trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl,phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted andisomerically pure derivatives. Groups R¹ and R² may be connected withother groups in compounds 13, 31 or 15 to form a bridge of 2 to 20atoms. Groups R³, R⁴ and R⁸ in compound 31 are selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Theboron substitutent R⁵ in compound 15 is selected from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl andallenyl. The boron substituents R⁶ and R⁷ which do not appear in theproducts, are selected from the groups consisting of: hydroxy, alkoxy,aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino,alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio,arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, includingsubstituted and isomerically pure derivatives. Groups R⁶ and R⁷ may beconnected together to form a bridge of 3 to 7 atoms.

The products 7 of the invention can be subsequently transformed toproduce new derivatives. For example, removing groups R¹ and R² canprovide primary amines, while joining two or more groups will result inthe formation of cyclic or polycyclic derivatives. A number of aminecomponents (13) can be used which include R¹ and R² groups that can beeasily removed in subsequent reactions. For example, benzylaminederivatives can be cleaved by hydrogenation, while others, such as thedi(p-anisyl)methylamino group or the trityl group, can be removed underacidic conditions which prevent facile racemization. Also, the use ofgroups R⁵ in the organoboron component, such as alkenyl or activatedaryl or heteroaryl, followed by oxidative cleavage gives new productswhere the R⁵ is a carbonyl group (aldehyde, ketone or carboxylic acid).One such example are compounds of the general formula 8, which include2-amino sugar derivatives that exist in a hemiacetal form.Alternatively, the use of carbonyl components 31 having a group R⁴ or R⁸consisting of a carbon atom attached to a hydroxyl group, as with manycarbohydrate derivatives, followed by oxidative diol cleavage canproduce new variations of compounds of the general formula 2.

Advantages and Improvements Over Existing Technology

Although there are many known methods for the synthesis of amines andamino acids, due to the vital importance of these compounds and the manyshortcomings of existing methods, any conceptually new and practicalmethod in this are is of special significance. The present method offersa number of advantages over existing methods, including:

1. This new method for amino acid synthesis is exceptionallyenvironmentally friendly and practical. The reactions can be done inwater or aqueous solvents at ambient temperature without using anytoxic, hazardous or corrosive materials, such as cyanides, isonitriles,strong acids, strong bases, organotin, organocopper or other highlyreactive organometallic compounds. Also, the reaction does not requirean inert atmosphere, and can be done in the air.

2. Unlike other methods which involve multistep manipulations of oneamino acid into another, the method of the invention offers directasymmetric construction of the amino acid structural unit from simplebuilding blocks (amine, α-ketoacid and boronic acid or boronate).

3. Existing procedures for preparing β,γ-unsaturated-α-amino acidssuffer either from low efficiency and low stereoselectivity or from theneed to use highly toxic reagents. The method of the invention offers adirect, efficient and highly versatile synthetic route to this importantclass of compounds.

4. The present method involves a smaller number of synthetic steps thanmost existing methods. All starting materials used in this type ofreaction are either commercially available or can be readily preparedfrom commercially available reagents by a one-step procedure.

5. Product isolation and purification in the present method is mucheasier than with existing methods. In most cases, the productprecipitates during the course of the reaction, and can be isolated by asimple filtration and washing, without the need for laboriouspurification procedures, such as extraction, distillation orchromatography.

The use of organoboron compounds, particularly boronic acids andboronates, as nucleophilic components for amino acid and amine synthesisis a new concept which offers a number of distinct features, includingthe following:

1. Organoboronic acids are often crystalline, easy to prepare and easyto handle compounds that are stable in air and water. They are also nontoxic and non hazardous. Although the synthesis and reactivity of thesemolecules has been studied extensively, the present method is the firstsuccessful example of their utilization in the synthesis of amines andamino acids.

2. Although the present method may appear similar to the Strecker andUgi methods for amino acid synthesis, it is conceptually different fromthem. The nucleophilic component in the Strecker and Ugi methods is anequivalent of the carboxylic acid moiety (cyanide or isonitrile) whilein the present method the nucleophilic component is a boron derivativeof the amino acid side chain. In this manner, the amine component iscombined with a more standard carbonyl component (e.g., glyoxylic acid)and the only real variable in each case is the amino acid side chain.The fact that the organoboron compounds used in the present method donot react directly with the carbonyl component gives them a uniqueadvantage and makes the overall reaction more selective.

3. The present method is highly versatile, allowing a high degree ofstructural variation in all of the reacting components. The process isalso a multi-component reaction, allowing the one-pot construction ofamino acid derivatives from several readily available building blocks.For these reasons, this method is easily applicable to the solid orliquid phase combinatorial synthesis of peptides and peptidomimetics.

4. The stereochemical control of the reaction can be accomplished notonly with the use of chiral amine and carbonyl components but also withchiral organoboron derivatives. An advantage of boron-based auxiliariesis that they can be easily introduced and can be efficiently recycledafter the reaction, thus making this method especially attractive forlarge scale applications.

5. Due to the facile synthesis of alkenyl and aryl boron derivatives,which proceed with complete control of geometry or positional isomerism,the present method is uniquely capable of furnishing isomerically pureproducts of this type.

6. Of special significance is the ability to directly use free aminoacids in this reaction. This leads to N-carboxymethyl amino acidderivatives, which are peptidomimetic compounds with importantpharmaceutical properties.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how toperform the processes of the present invention, and are not intended tolimit the scope of what the inventors regard as their invention. Effortshave been made to ensure accuracy with respect to numbers used (e.g.amounts, temperature, etc.) but some experimental errors and deviationsshould be accounted for. Unless indicated otherwise, parts are parts byweight, molecular weight is weight average molecular weight, temperatureis in degrees centigrade, and pressure is at or near atmospheric.

Tables I-VII, summarize a number of reactions from several types ofamines, carbonyls and organoboron compounds that have been utilized inthis process. Subsequently, representative experimental procedures andstructural data of the obtained products are given.

TABLE I Conditions Product Yield

91%

87%

90%

95%

54%

68%

96%

TABLE II Conditions Product Yield

89

94%

78%

76%

87%

52%

TABLE III Chiral amine Conditions Product Yield % (% de)

88% (66% de)

88% (89% de)

91% (83% de)

78% (99% de)

78% (99% de)

76% (99% ee)

TABLE IV Amino acid Conditions Product Yield % (% de)

79% (99% de)

89% (99% de)

85% (94% de)

83% (24% de)

47% (>99% de)

95% (>99% de) Enalaprilat 95% (>99% de)

TABLE V Conditions Product Yield

X = H 84% X = F 50% X = Br 71% X = OMe 85% X = CH═CH₂ 90%

92%

80%

TABLE VI Conditions Product Yield % (% de)

75%

54% (>99% de)

88% (>99% de)

72% (>99% de)

78%

88%

TABLE VII Conditions Product Yield % (% de)

74% (>99% de) (D)-Ribose

EtOH, 25° C.

77% (>99% de) (D)-Arabinose

EtOH, 25° C.

67% (>99% de) (D)-Xylose

EtOH, 25° C.

(D)-Arabinose

EtOH, 25° C.

Example 1

Preparation of (E)-2-(N-adamantyl)-amino-4-phenyl-3-butenoic acid.

To a stirred solution of glyoxylic acid monohydrate (88 mg, 0.957 mmol)in dichloromethane (7 mL) was added 1-adamantanamine (144 mg, 0.957mmol) in one portion. After 5 min, (E)-2-phenylethenyl boronic acid (141mg, 0.957 mmol) was added and the reaction mixture was stirredvigorously at room temperature for 12 hours. The precipitate wasisolated by filtration, washed with dichloromethane (15 mL) and coldacetone (10 mL) and dried under vacuum to give(E)-2-(N-adamantyl)-amino-4-phenyl-3-butenoic acid (284 mg, 96% yield).¹H-NMR (360 MHz, DCl/D₂O) δ 6.8-7.2 (m, 5H), 6.68 (d, J=15.7 Hz, 1H),5.96 (dd, J=15.7 Hz, 9.2 Hz, 1H), 4.63 (d, J=9.2 Hz, 1H), 1.2-1.8 (m,15H). ¹³C-NMR (90 MHz, D₂O-DCl) δ 170.9, 140.2, 135.5, 130.3, 129.8,128.0, 119.1, 62.0, 56.9, 40.8, 39.4, 35.5, 29.8. Anal. Calcd forC₂₁H₂₉NO₂: C, 77.03; H, 8.93; N, 4.28. Found: C, 77.01; H, 8.83; N,4.34.

Example 2

Preparation of (E)-2-(N-benzyl)-amino-4-phenyl-3-butenoic acid.

To a stirred solution of benzylamine (120 mg, 1.120 mmol) in ethanol (5mL) was added dropwise the solution of glyoxylic acid monohydrate (103mg, 1.120 mmol) in ethanol (3 mL). After 5 min, (E)-2-phenylethenylboronic acid (165 mg, 1.115 mmol) was added in one portion and thereaction mixture was stirred vigorously at room temperature for 12hours. The precipitate was isolated by filtration, washed withdichloromethane (15 mL), cold acetone (10 mL) and dried under vacuum togive (E)-2-(N-benzyl)-amino-4-phenyl-3-butenoic acid (259 mg, 87%yield). ¹H-NMR (360 MHz, d₆-DMSO ) δ 7.2-7.5 (m, 10H), 6.68 (d, J=15.6Hz, 1H), 6.22 (dd, J=15.6 Hz, 7.9 Hz, 1H), 3.90 (s, 2H), 3.82 (d, J=7.9Hz, 1H).

¹³C-NMR (90 MHz, d₆-DMSO) δ 171.23, 136.31, 133.22, 129.04, 128.68,128.47, 128.37, 128.18, 127.97, 127.74, 126.90, 63.49, 49.21.

Anal. Calcd for C₁₇H₁₇NO₂: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.31;H, 6.44; N, 5.23.

Example 3

Preparation of (E)-2-morpholino-3-octenoic acid.

To a stirred solution of glyoxylic acid monohydrate (80 mg, 0.87 mmol)in ethanol (6 mL) was added morpholine (76 mg, 0.87 mmol) in oneportion. After 5 min (E)-1-hexenyl boronic acid (121 mg, 0.82 mmol) wasadded. The reaction mixture was heated at 50° C. for 36 hours, afterwhich time precipitate was isolated by filtration, washed with coldethanol (10 mL) and dried under vacuum to give(E)-2-morpholino-3-octenoic acid (177 mg,78% yield). ¹H-NMR (360 MHz,d₆-DMSO) δ 5.65 (dt, J=16.1 Hz, 7.0 Hz, 1H), 5.28 (dd, J=16.1 Hz, 9.1Hz, 1H), 4.81 (d, J=9.1 Hz, 1H), 2.50 (m, 2H), 1.1 (m, 4H), 0.7 (t,J=7.1 Hz, 3H). ¹³C-NMR (90 MHz, d₆-DMSO) δ 171.1, 136.7, 127.4, 68.8,62.5, 56.7, 31.7, 30.2, 22.1, 13.9. HRMS-CI (M⁺+1) Calcd for C₁₂H₂₁NO₃:228.1521, Found: 228.1513.

Example 4

Preparation of D-homophenylalanine.

To a stirred solution of glyoxylic acid monohydrate (291 mg, 3.163 mmol)in dichloromethane (14 mL) was added (S)-(−)-2-phenylglycinol (434 mg,3.163 mmol) in one portion. After 5 min (E)-2-phenylethenyl boronic acid(469 mg, 3.169 mmol) was added. and the reaction mixture was stirredvigorously at room temperature for 12 hours. The precipitate wasisolated by filtration, washed with cold dichloromethane (15 mL) andacetone (10 mL) and dried under vacuum to give the expected adduct (733mg, 78% yield, >99% de). ¹H-NMR (360 MHz, d₆-DMSO) δ 7.2-7.5 (m, 10H),6.54 (d, J=15.2 Hz, 1H), 6.20 (dd, J=15.2 Hz, 7.3 Hz, 1H), 3.84 (m, 1H),3.64 (d, J=7.3 Hz, 1H), 3.45 (d, J=7.1 Hz, 2H).

¹³-NMR (90 MHz, d₆-DMSO) δ 172.83, 139.79, 136.23, 131.07, 128.62,128.34, 127.68, 127.51, 126.95, 126.38, 126.25, 65.97, 63.02, 60.96.HRMS-CI(M⁺+1) calcd 298.1365, obsd 298.1449. Anal. Calcd for C₁₈H₁₉NO₃:C, 72.71; H, 6.44; N, 4.71. Found: C, 72.27; H, 6.41 N, 4.69.

To a suspension of the above compound (150 mg, 0.505 mmol) andPearlman's catalyst (50 mg) in methanol (10 mL) was added a hydrochloricacid solution in diethyl ether (3 mL) and the reaction mixture wasvigorously stirred under an atmosphere of hydrogen gas for 48 hours. Thecatalyst was removed by filtration and the solution was evaporated todryness. The resulting residue was suspended in dichloromethane (10 mL)and the white precipitate was isolated by filtration, washed withdichloromethane (10 mL) and dried under vacuum to giveD-homophenylalanine (69 mg, 76% yield). Using Mosher's acid chloride theproduct was determined to have 98% ee. All properties of the compoundobtained were consistent with a commercially available authentic sample.

¹H-NMR (360 MHz, d₆-DMSO) δ 7.2-7.5 (m, 5H), 3.83 (t, J=6.1 Hz, 1H),2.70 (m, 2H), 2.08 (m, 2H). ¹³C-NMR (90 MHz, d₆-DMSO) δ 170.8, 140.5,128.5, 128.3, 126.2, 51.6, 31.9, 30.4. HRMS-CI (M⁺+1) calcd 180.0946,obsd 180.1029. [α]²¹ _(D)=−46.0° (C=1, 3N HCl).

Example 5

Preparation of (E)-2-amino-4-phenyl-3-butenoic acid.

To a stirred solution of glyoxylic acid (110 mg, 1.2 mmol) in toluene(12 mL) was added di-(p-anisyl)-methylamine (291 mg, 1.2 mmol) in oneportion. After 1 min, 2-phenylethenyl boronic acid (177 mg, 1.2 mmol)was added and the reaction mixture was stirred vigorously for 12 hours.The precipitated product was isolated by filtration, washed withdichloromethane (15 mL), toluene (10 mL) and dried under vacuum to givethe expected product (430 mg, 89% yield). ¹H-NMR (360 MHz, CD₃OH) d6.8-7.5 (m, 13H), 6.60 (d, J=15.5 Hz, 1H), 6.25 (dd, J=15.5 Hz, 9.5 Hz,1H), 5.49 (s, 1H), 4.00 (d, J=9.5 Hz, 1H), 3.75 (s, 6H), 2.3 (s, 1H).

¹³C-NMR (360 MHz, CD₃OH) d 171.55, 161.60, 161.52, 138.91, 137.06,130.56, 130.39, 129.92, 129.74, 129.64, 129.51, 129.20, 128.84, 127.89,126.30, 121.54, 115.66, 115.52, 65.06, 65.02, 55.81.

The above product (210 mg, 0.52 mmol) was dissolved in 50% acetic acid(10 mL) and heated under reflux at 80° C. for 20 min. After cooling toambient temperature, the reaction mixture was further acidified with 3NHCl (3 mL) and extracted with diethyl ether (2×10 mL). Evaporation ofwater resulted in a solid, which was transferred to the glass filterwith the help of a little amount of dichloromethane and dried to givethe hydrochloride salt of (E)-2-amino-4-phenyl-3-butenoic acid (75 mg,81% yield). ¹H-NMR (360 MHz, DCl/D₂O) δ 6.6-6.8 (m, 5H), 6.21 (d, J=15.9Hz, 1H), 5.60 (dd, J=15.9 Hz, 9.0 Hz, 1H), 4.12 (d, J=9.0 Hz, 1H).¹³C-NMR (90 MHz, D₂O-DCl) δ 170.2, 138.6, 134.8, 129.2, 128.9, 127.0,118.0, 54.7.

Example 6

Preparation of (E)-2-(N-p-methoxyphenyl)-amino-4-phenyl-3-butenoic acid.

To a stirred solution of glyoxylic acid monohydrate (88 mg, 0.957 mmol)in dichloromethane (7 mL) was added p-methoxyaniline (118 mg, 0.958mmol) in one portion. After 5 min, (E)-2-phenylethenyl boronic acid (141mg, 0.957 mmol) was added and the reaction mixture was stirredvigorously at room temperature for 12 hours. The precipitate wasisolated by filtration, washed with dichloromethane (15 mL) and coldacetone (10 mL), and dried under vacuum to give the amino acid product(284 mg, 96% yield).

¹H-NMR (360 MHz, d₆-DMSO) δ 6.5-7.5 (m, 10H), 6.35 (dd, J=15.5 Hz, 5.9Hz, 1H), 4.62 (d, J=5.9 Hz, 1H), 3.66 (s, 3H).

¹³C-NMR (90 MHz, d₆-DMSO) δ 173.3, 151.3, 141.3, 136.1, 131.6, 128.7,127.8, 126.4, 126.3, 114.4, 114.0, 58.9, 55.8.

Anal. Calcd for C₁₇H₁₇NO₃: C, 72.07; H, 6.05; N, 4.94. Found: C, 72.10;H, 6.02; N, 4.85.

Example 7

This compound was prepared as in example 6, but substitutingaminodiphenylmethane for p-methoxyaniline and 2-(4-methylphenyl) ethenylboronic acid for 2-phenylethenyl boronic acid. ¹H-NMR (360 MHz, d₆-DMSO)δ 7.0-7.5 (m, 14H), 6.48 (d, J=16.0 Hz, 1H), 6.20 (d, J=16.0 Hz, 1H),4.93 (s, 1H), 2.26 (s, 3H), 1.22 (s, 3H).

¹³C-NMR (90 MHz, d₆-DMSO) δ 175.7, 145.7, 145.6, 136.9, 133.63, 131.8,129.14, 128.8, 128.3, 127.1, 127.0, 126.6, 126.3, 63.9, 62.2, 22.7,20.8.

Anal. Calcd for C₂₅H₂₅NO₂: C, 80.83; H, 6.78; N, 3.77. Found: C, 81.02;H, 6.72; N, 3.74.

Example 8

This compound was prepared as in example 7, but substituting2-bromo-2-phenyl boronic acid for 2-(4-methylphenyl) ethenyl boronicacid. ¹H-NMR (360 MHz, d₆-DMSO) δ 7.1-7.6 (m, 15H), 6.48 (d, J=8.7 Hz,1H), 4.95 (s, 1H), 4.15 (d, J=8.7 Hz, 1H).

¹³C-NMR (90 MHz, d₆-DMSO) δ 172.2, 143.4, 138.4, 129.5, 129.1, 128.9,128.4, 128.3, 127.3, 127.2, 126.9, 63.9, 61.5.

Anal. Calcd for C₂₃H₂₀BrNO₂: C, 65.41; H, 4.77; N, 3.32. Found: C,65.66; H, 4.97; N, 3.22.

Example 9

The reaction was run as in example 6, for 48 hours in dichloromethane in43% isolated yield, >99% de.

¹H NMR (360 MHz, DMSO-d₆) δ 7.00-7.48 (m, 10H), 6.25 (s, 1H), 3.79 (m,1H), 3.59 (s, 1H), 3.45 (m, 2H), 1.82 (s, 3H).

¹³C NMR (90 MHz, DMSO-d₆) δ 173.2, 140.5, 137.2, 135.7, 129.0, 128.6,128.5, 128.1, 127.9, 127.8, 126.9, 67.5, 66.2, 64.2, 15.4.

Example 10

Preparation of (±)-N-(diphenylmethyl)-α-phenylalycine.

To a stirred solution of glyoxylic acid monohydrate (92 mg, 1 mmol) indichloromethane (7 mL) was added aminodiphenylmethane (183 mg, 1 mmol),followed by phenylboronic acid (122 mg, 1 mmol). After the flask waspurged with argon and sealed, the reaction mixture was stirredvigorously at room temperature for 48 h. The resulting precipitate wasisolated by filtration, washed with dichloromethane (10 mL) and purifiedby ion-exchange chromatography (Dowex 50W-X8) to give pure(±)-N-(diphenylmethyl)-α-phenylglycine (266 mg, 84% yield).

¹H-NMR (360 MHz, DMSO-d₆) δ 7.0-7.8 (m, 15H), 4.78 (s, 1H), 4.17 (s,1H); ¹³C-NMR (90 MHz, DMSO-d₆) δ 172.8, 142.4, 133.6, 129.6, 128.1,127.5, 127.1, 126.9, 126.7, 63.6, 62.2.

Anal. calcd for C₂₁H₁₉NO₂: C, 79.47; H, 6.03; N, 4.41; found: C, 79.48;H, 6.17; N, 4.32.

Example 11

Preparation of (±)-N-(diphenylmethyl)-α-(4-fluorophenyl)glycine.

Prepared similarly to (±)-N-(diphenylmethyl)-α-phenylglycine in 50%yield. ¹H-NMR (250 MHz, DMSO-d₆) δ 7.15-7.92 (m, 14H), 4.72 (s, 1H),4.12 (s, 1H); ¹³C-NMR (63 MHz, DMSO-d₆) δ 173.2, 163.3, 159.7, 143.3,143.2, 134.7, 129.3, 129.2, 128.3, 128.2, 127.0, 115.2, 114.9, 63.9,61.8; ¹⁹F-NMR (339 MHz, DMSO-d₆) δ −114.6 (br).

Example 12

Preparation of (±)-N-(diphenylmethyl)-α-(4-methoxyphenyl)glycine.

Prepared similarly to (±)-N-(diphenylmethyl)-α-phenylglycine in toluene(85% yield). ¹H-NMR (250 MHz, acetone-d₆) δ 7.16-7.45 (m, 12H),6.89-6.92 (m, 2H), 4.80 (s, 1H), 4.20 (s, 1H) 3.78 (s, 3H); ¹³C-NMR (63MHz, acetone-d₆) δ 174.2, 160.3, 144.6, 131.4, 129.7, 129.5, 129.3,129.2, 128.2, 127.9, 127.8, 114.7, 114.6, 65.1, 62.8, 55.5.

Example 13

Preparation of (±)-α-phenylglycine hydrochloride.

To a stirred solution of glyoxylic acid monohydrate (184 mg, 2 mmol) intoluene (10 mL) was added di(p-anisyl)methyl amine (486 mg, 2 mmol),followed by phenylboronic acid (244 mg, 2 mmol). After the flask waspurged with argon and sealed, the reaction mixture was stirredvigorously at room temperature for 48 h. Upon evaporation of the solventthe resulting crude product was dissolved in 70% aqueous acetic acid (10mL) and heated under reflux at 80° C. for 40 min. After cooling to roomtemperature the reaction mixture was further acidified with 3N aqueousHCl (5 mL) and extracted with diethyl ether (3×20 mL). Evaporation ofthe aqueous layer gave a solid, which was washed with dichloromethaneand dried to give (±)-α-phenylglycine hydrochloride (233 mg, 62% yield).¹H-NMR (250 MHz, methanol-d₄) δ 7.41-7.51 (br, 5H), 5.18 (s, 1H);¹³C-NMR (63 MHz, methanol-d₄) δ 170.7, 131.0, 130.5, 129.7, 129.1, 57.6;HRMS-CI calcd for C₈H₉NO₂ (M⁺+1) 152.0633, obsd 152.0591.

Example 14

Preparation of (±)-N-(Diphenylmethyl)-α-(3-thienyl)glycine:

Prepared in 92% yield. ¹H-NMR (360 MHz, DMSO-d₆) δ 7.20-7.75 (m, 13 H),4.77 (s, 1H), 4.15 (s, 1H); ¹³C-NMR (90 MHz, DMSO-d₆) δ 173.3, 143.6,143.2, 139.2, 122.7, 128.4, 127.1, 127.0, 126.8, 126.3, 64.1, 58.7.

Example 15

Preparation of (±)-N-(p-Anisyl)-α-(2-thienyl)glycine.

Prepared in ethanol over 12 h (79% yield). ¹H-NMR (250 MHz, DMSO-d₆) δ7.42 (d, J=5.2 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 6.98 (dd, J=5.2 Hz,J=3.5 Hz, 1H), 6.65 (br, 4H), 5.29 (s, 1H), 3.61 (s, 3H); ¹³C-NMR (63MHz, DMSO-d₆) δ 172.7, 151.9, 142.4, 141.2, 127.1, 126.2, 125.8, 114.8,114.7, 56.9, 55.5.

Example 16

Preparation of (±)-N-α-(2-benzo[b]thienyl) glycine hydrochloride.

Prepared in dichloromethane over 12 hours (80% yield). ¹H NMR (360 MHz,DMSO-d₆) δ 7.35-8.21 (m, 5H), 5.55 (s, 1H); ¹³C NMR (90 MHz, DMSO-d₆) δ168.6, 139.4, 138.5, 135.2, 125.6, 125.4, 125.0, 124.2, 122.7, 51.7;HRMS-CI calcd for C₁₀H₉NO₂S (M⁺+1) 208.0354, obsd 208.0387.

Example 17

Preparation of (±)-N-α-(2-thienyl)glycine hydrochloride.

Prepared in dichloromethane over 12 hours (79% yield). ¹H-NMR (360 MHz,DCl/D₂O) δ 6.48 (d, J=4.8 Hz, 1H), 6.21 (d, J=3.7 Hz, 1H), 5.99 (dd,J=4.8 Hz, J=3.7 Hz, 1H), 4.50 (s, 1H); ¹³C-NMR (90 MHz, DCl/D₂O) δ169.9, 131.6, 130.5, 129.8, 128.4, 52.0; HRMS-CI calcd for C₆H₇NO₂S(M⁺+1) 158.0197, obsd 158.0199.

Example 18

Reaction was run similarly to example 6, for 12 hours indichloromethane, 90% yield. ¹H NMR (360 MHz, DMSO-d₆) δ 7.46 (d, J=4.8Hz, 1H), 7.15 (d, J=3.2 Hz, 1H), 7.00 (dd, J=4.8 Hz, 3.2 Hz, 1H), 4.52(s, 1H), 1.31-2.52 (m, 17H). ¹³C NMR (90 MHz, DMSO-d₆) δ 170.2, 126.8,126.7, 126.3, 126.0, 61.3, 58.6, 39.6, 36.4, 32.6, 27.6.

Example 19

Preparation of 1-morpholino-1.3-diphenyl-2-propene.

The synthesis of substituted allylamines cannot be accomplished by thesimple mixing of an aldehyde or ketone with an amine and a boronic acid.The reaction is also slow with aminals or preformed iminium salts.However, aminals can react in the presence of boron trifluoride to givethe expected products. In another variation, the boronic acid can bereacted with potassium hydrogen fluoride to give the correspondingtrifluoroborate salt, which can react readily with aminals in thepresence of trimethylsilyl chloride.

To a vigorously stirred solution of (E)-2-phenylethenyl boronic acid(200 mg, 1.351 mmol) in methanol (10 mL) was slowly added excesssaturated potassium hydrogen fluoride (15 mL, of a 4.5 M solution).After 15 min, the precipitated product was collected and washed withcold methanol. Recrystallization from minimal acetonitrile produced pure(E)-2-phenylethenyl-trifluoroborate (229 mg, 81% yield). ¹H-NMR (360MHz, d₃-acetonitrile) δ 7.1-7.4 (m, 5H), 6.6 (d, J=18.8 Hz, 1H), 6.28(dq, J=18.8 Hz, 4.1 Hz, 1H).

Alternative procedure: To a suspension of(E)-2-phenylethenyltrifluoroborate (100 mg, 0.476 mmol) and4,4′-benzylidenedimorpholine (124 mg, 0.473 mmol) in dry tetrahydrofuran(10 mL) stirred under nitrogen at room temperature was addedchlorotrimethylsilane (102 mg, 0.940 mmol). After stirring at roomtemperature for 6 hours the reaction was heated at 50° C. for 3 hoursand the mixture was poured into brine (50 mL), extracted with ether(3×50 mL), and the combined organic layers were dried over magnesiumsulfate. Product purification by flash column chromatography (silica,1:4ethyl acetate/hexanes) afforded pure 1-morpholine-1,3-diphenyl-2-propeneas a colorless oil (90 mg, 68% yield). ¹H-NMR (250 MHz, d6-acetone) δ7.2-7.5 (m, 10H), 6.65 (d, J=15.7Hz, 1H), 6.36 (dd, J=15.7Hz, 8.8Hz,1H), 3.84 (d, J=8.8 Hz, 1H), 3.65 (t, J=6.8Hz, 4H), 2.45 (t, J=6.8 Hz,4H).

Example 20

A variation that does not require any additives is the reaction oforganoboronic acids with nitrones which gives smoothly the correspondingproduct:

A typical experimental procedure was as follows: To a stirred solutionof N-α-diphenyl nitrone (115 mg, 0.584 mmol) in tetrahydrofuran (7 mL)was added (E)-2-phenylethenyl boronic acid (86 mg, 0.584 mmol) and thereaction mixture was stirred in the dark at room temperature for 5hours. After this time the mixture was poured into brine (50 mL),extracted with ether (3×50 mL) and the combined organic layers weredried over magnesium sulfate. Product purification by flash columnchromatography (silica, 3:7 ethyl acetate/hexanes) afforded pure1-(N-hydroxy-N-phenyl)-1,3-diphenyl-2-propene (120 mg, 68% yield).¹H-NMR (250 MHz, d₆-benzene) δ 6.82-7.5 (m, 15H), 6.75 (dd, J=16.1 Hz,J=7.8 Hz, 1H), 6.36 (d, J=16.1 Hz, 1H), 5.13 (d, J=7.8 Hz, 1H).

Example 21

Following the procedure of example 20, the reaction was run for 16 hoursin MeOH, 82% yield. ¹H NMR (360 MHz, DMSO-d₆) δ 7.18-7.51 (m, 10H), 6.71(d, J=15.9 Hz, 1H), 6.37 (dd, J=15.9 Hz, 9.1 Hz, 1H), 4.02 (d, J=9.1 Hz,1H), 3.91 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H). ¹³C NMR (63 MHz,DMSO-d₆) δ 171.6, 138.4, 136.1, 134.3, 129.2, 128.7, 128.0, 127.9,126.7, 126.5, 124.6, 74.1, 60.7.

Example 22

A mixture of L-leucine (100 mg, 0.762 mmol), glyoxylic acid monohydrate(70 mg, 0.762 mmol) and (E)-2-phenylethenyl boronic acid (113 mg, 0.764mmol) in water (8 mL) was stirred vigorously for 24 hours at 50 C. Theprecipitate was isolated by filtration, washed with methanol (10 mL) anddried under vacuum to give(E)-2-[(S)-N-(-1′-carboxy-3′-methylbutyl)-amino-4-phenyl-3-butenoic acid(247 mg, 85% yield, 94% de). ¹H-NMR (360 MHz, d₆-DMSO) δ 7.2-7.5 (m,5H), 6.62 (d, J=15.3 Hz, 1H), 6.18 (dd, J=15.3 Hz, 8.1 Hz, 1H), 3.82 (d,J=8.1 Hz, 1H), 3.32 (m, 1H), 1.7 (m, 2H), 1.4 (m, 1H), 0.85 (d, 6.8 Hz,6H).

Example 23

A mixture of L-phenylalanine (100 mg, 0.606 mmol), glyoxylic acidmonohydrate (56 mg, 0.608 mmol) and (E)-2-phenylethenyl boronic acid (89mg, 0.601 mmol) in methanol (8 mL) was stirred vigorously for 24 hours.The precipitate was isolated by filtration, washed with methanol (10 mL)and dried under vacuum to give(E)-2-[(S)-N-(1′-carboxy-2′phenyl)-amino-4-phenyl-3-butenoic acid (160mg, 82% yield, 99% de). ¹H NMR (360 MHz, DMSO-d₆) δ 7.18-7.45 (m, 10H),6.58 (d, J=16.0 Hz, 1H), 6.10 (dd, J=16.0 Hz, 8.1 Hz, 1H), 3.91 (d,J=7.8 Hz, 1H), 3.45 (t, J=6.4 Hz, 1H), 2.88 (m, 2H). ¹³C NMR (90 MHz,DMSO-d₆) δ 174.9, 172.9, 138.0, 137.8, 136.1, 132.6, 129.4, 128.6,127.7, 126.8, 126.4, 126.3, 61.7, 61.0, 59.6.

Example 24

Prepared similarly to example 23, except that 2-furly boronic acid wasused instead of (E)-2-phenylethenyl boronic acid. The reaction was runfor 36 hours in methanol to give 59% yield. ¹H NMR (360 MHz, DMSO-d₆) δ7.21-7.65 (m, 6H), 6.37-6.47 (m, 2H), 4.42 (s, 1H), 3.39 (t, J=6.3 Hz,1H), 3.16 (s, 1H), 2.87 (m, 2H). ¹³C NMR (90 MHz, DMSO-d₆) δ 174.0,171.1, 151.3, 142.7, 137.7, 129.2, 128.0, 126.2, 110.4, 108.2, 59.2,56.8, 38.1.

Example 25

Alanine-proline (1,000 mg, 5.37 mmol), glyoxylic acid monohydrate (544mg, 5.91 mml) and 2-phenylethenyl boronic acid (1,192 mg, 8 mmol) werevigorously stirred together in water (7 mL) for 48 hours. Theprecipitate was filtered, washed with acetone (2×10 mL) and dried togive a single crystalline product (1,488 mg, 80% yield, >99% de) thestructure of which was confirmed with X-ray crystallography. ¹H NMR (360MHz, DCl/D₂O) δ 7.10-7.25 (br, 5H), 6.92 (d, J=15.6 Hz, 1H), 5.78 (dd,J=15.6 Hz, 9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H), 4.15 (q, J=6.8 Hz, 1H),3.84 (m, 1H), 3.20 (m, 2H), 1.58 (m, 2H), 1.41 (d, J=6.8 Hz, 3H),1.01-1.35 (m, 2H). ¹³C NMR (90 MHz, DCl/D₂O) δ 174.2, 168.7, 168.2,142.6, 133.4, 130.4, 129.3, 127.1, 114.7, 62.3, 59.4, 54.0, 47.4, 28.0,24.0, 15.1. HRMS-CI calcd for C₁₈H₂₂N₂O₅ (M+H⁺) 347.1528, found347.1598. Anal. Calcd for C₁₈H₂₂N₂O₅: C, 62.42; H, 6.40; N, 8.09. Found:C, 62.46; H, 6.41 N, 8.02. This compound was hydrogenated in methanolwith Pd/C as catalyst to give pure enalaprilat.

Example 26

To the suspension of glycolaldehyde dimer (43 mg, 0.36 mmol) in toluene(7 mL) was added aminodiphenylmethane ( 132 mg, 0.72 mmol), followed by(E)-2-phenylethenyl boronic acid (164 mg, 0.72 mmol). The reaction flaskwas sealed and stirred vigorously for 24 hours at ambient temperature.After the evaporation of volatiles, the product was isolated by flashcolumn chromatography on silica gel using ethylacetate-hexanes (3:7) asthe eluent to give 247 mg of product, 84% yield. ¹H NMR (250 MHz, CDCl₃)δ 7.21-7.55 (m, 15H), 6.10 (d, J=8.4 Hz, 1H), 5.03 (s, 1H), 3.88 (m,1H), 3.72 (dd, J=10.8 Hz, 4.2 Hz, 1H), 3.51 (dd, J=10.8 Hz, 8.0 Hz, 1H).

¹³C NMR (90 MHz, CDCl₃) δ 144.1, 142.9, 139.1, 130.9, 128.9, 128.6,128.3, 127.6, 127.2, 64.6, 63.8, 60.1.

HRMS-CI calcd for C₂₃H₂₂BrNO (M+H⁺) 408.0884, found 408.0949.

Example 27

Synthesis performed as in example 35, except that ethanol was used as areaction solvent. 77% yield.

¹H NMR (250 MHz, CDCl₃) δ 6.81-7.41 (m, 8H), 4.18 (dd, J=10.0 Hz, J=4.9Hz, 1H), 3.94 (t, J=10.6 Hz, 1H), 3.67 (m, 1H), 3.65 (d, J=12.7 Hz, 1H),3.41 (d, J=12.7 Hz, 1H), 2.21 (s, 3H).

¹³C NMR (90 MHz, CDCl₃) δ 138.6, 137.1, 128.9, 128.4, 127.3, 126.6,126.4, 124.8, 62.6, 61.3, 58.3, 36.5.

HRMS-CI calcd for C₁₄H₁₇NOS (M+H⁺) 248.1031, found 248.1114.

Example 28

To the suspension of dihydroxyacetone (90 mg, 1 mmol) in ethyl alcohol(7 mL) was added dibenzylamine (197 mg, 1 mmol), followed bybenzo[b]thiophene-2-boronic acid (178 mg, 1 mmol). Reaction mixture wasstirred vigorously for 6 hours at ambient temperature. Precipitatedproduct was isolated by filtration, washed with cold ethyl alcohol (2×10mL) and dried. Obtained 250 mg of product, 62% yield. ¹H NMR (360 MHz,acetone-d₆) δ 7.01-8.00 (m, 15H), 4.73 (d, J=11.4 Hz, 2H), 4.47 (d,J=11.4 Hz, 2H), 3.92 (s, 4H).

¹³C NMR (90 MHz, acetone-d₆) δ 144.4, 140.3, 139.9, 134.1, 129.4, 128.7,127.4, 126.0, 125.6, 125.3, 125.1, 124.9, 124.6, 124.1, 123.2, 123.1,68.6, 63.9, 54.7. HRMS-CI calcd for C₂₅H₂₅NO₂S (M+H⁺) 404.1606, found404.1684.

Example 29

To the solution of salicylaldehyde (122 mg, 1 mmol) in ethyl alcohol (7mL) was added morpholine (87 mg, 1 mmol), followed by(E)-2-phenylethenyl boronic acid (148 mg, 1 mmol). The reaction flaskwas sealed and stirred vigorously for 24 hours at ambient temperature.After the evaporation of volatiles, the product was isolated by flashcolumn chromatography on silicagel using ethylacetate-hexanes (2:8) asthe eluent. Obtained 260 mg of product, 88% yield. ¹H NMR (360 MHz,acetone-d₆) δ 7.12-7.91 (m, 7H), 6.75 (m, 2H), 6.74 (d, J=15.9 Hz, 1H),6.46 (dd, J=15.9 Hz, 9.5 Hz, 1H), 4.18 (d, J=9.5 Hz, 1H), 3.69 (t, J=5.0Hz, 4H), 2.82 (s, 1H), 2.60 (br, 4H). ¹³C NMR (90 MHz, benzene-d₆) δ157.5, 136.6, 134.0, 129.4, 129.1, 128.8, 128.1, 126.9, 126.7, 124.6,119.8, 117.3, 74.4, 66.8, 51.4. HRMS-CI calcd for C₁₉H₂₁NO₂ (M+H⁺)296.1572, found 296.1648.

Example 30

(D)-Glyceraldehyde (520 mg, ca. 75% in water, ca. 4.33 mmol) wasdissolved in EtOH (15 mL) and to this solution was addedaminodiphenylmethane (793 mg, 4.33 mmol), followed by(E)-2-phenylethenyl boronic acid (652 mg, 4.4 mmol). The reaction flaskwas sealed with plastic stopper and reaction mixture was vigorouslystirred for 24 hours at ambient temperature. After the removal ofvolatiles, the residue was suspended in 6 N hydrochloric acid (20 mL)and heated with vigorous stirring at 60 C for 1 hour. After that time,the solution was cooled and filtered. The precipitate on the filter waswashed with cold water (2×10 mL), ethylacetate (3×20 mL) and dried.Obtained 1201 mg of pure product (77% yield, >99% de). ¹H NMR (250 MHz,CD₃OD) δ 7.30-7.65 (m, 15H), 6.60 (d, J=16 Hz, 1H), 6.33 (dd, J=16 Hz,8.5 Hz, 1H), 5.59 (s, 1H), 4.18 (m, 1H), 3.93 (dd, J=8.5 Hz, 3.0 Hz,1H), 3.57 (dd, J=10.9 Hz, 5.6 Hz, 1H), 3.40 (dd, J=10.9 Hz, 7.6 Hz, 1H).¹³C NMR (63 MHz, C₆D₆) δ 144.8, 143.3, 137.1, 134.0, 129.0, 128.8,128.7, 128.1, 127.9, 127.7, 127.4, 127.3, 126.8, 74.2, 65.2, 64.0, 61.5.HRMS-CI calcd. for C₂₄H₂₅NO₂ (M+H⁺) 360.1885, found 360.1949.

Example 31

(DL)-Glyceraldehyde (100 mg, 1.11 mmol) was dissolved in EtOH (10 mL)and to this solution was added N-benzylmethylamine (134 mg, 1.11 mmol),followed by 2-thiophene boronic acid (143 mg, 1.12 mmol). The reactionflask was sealed with a plastic stopper and the reaction mixture wasvigorously stirred for 24 hours at ambient temperature. After theremoval of volatiles, the residue was redissolved in dichloromethane andpurified by flash chromatography on silicagel usingdichloromethane-methanol (800:70) as the eluent. Obtained 246 mg of pureproduct (80% yield, >99% de). ¹H NMR (360 MHz, acetone-d₆) δ 7.12-7.49(m, 8H), 4.20 (m, 1H), 3.92 (d, J=7.7 Hz, 1H), 3.65 (m, 2H), 3.61 (d,J=13.2 Hz, 1H), 3.40 (d, J=13.2 Hz, 1H), 2.14 (s, 3H).

¹³C NMR (63 MHz, acetone-d₆) δ 140.2, 139.0, 129.6, 129.0, 128.0, 127.7,126.9, 125.3, 72.3, 66.3, 66.1, 59.9, 38.4. HRMS-CI calcd. forC₁₅H₁₉NO₂S (M+H⁺) 278.1136, found 278.1218.

Example 32

The reaction was performed as in example 31 in 73% yield, >99% de. ¹HNMR (360 MHz, acetone-d₆) δ 7.25-7.35 (m, 5H), 5.69 (dt, J=15.4 Hz, 5.4Hz, 1H), 5.47 (dd, J=15.4 Hz, 9.6 Hz, 1H), 3.84 (m, 1H), 3.68 (d, J=13.4Hz, 1H), 3.60 (dd, J=10.7 Hz, 5.6 Hz, 1H), 3.51 (dd, J=10.7 Hz, 6.1 Hz,1H), 3.43 (d, J=13.4 Hz, 1H), 2.90 (dd, J=9.6 Hz, 8.0 Hz, 1H), 2.18 (s,3H), 2.05 (m, 2H), 1.8 (m, 4H), 0.9 (t, J=6.9 Hz, 3H). ¹³C NMR (63 MHz,acetone-d₆) δ 140.5, 137.3, 129.7, 129.0, 127.6, 125.5, 71.8, 69.6,66.8, 59.7, 38.5, 33.0, 32.4, 22.8, 14.2. HRMS-CI calcd. for C₁₇H₂₇NO₂(M+H⁺) 278.2042, found 278.2031.

Example 33

The reaction was performed as in example 31 in 72% yield, >99% de. ¹HNMR (250 MHz, CDCl₃) δ 6.98-7.45 (m, 9H), 4.35 (m, 1H), 3.86 (s, 3H),3.79 (d, J=5.7 Hz, 2H), 3.70 (d, J=9.4 Hz, 1H), 3.56 (d, J=13.1 Hz, 1H),3.38 (d, J=13.1 Hz, 1H), 2.21 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 159.1,138.2, 130.8, 128.9, 128.4, 127.2, 125.5, 113.6, 70.6, 68.4, 66.8, 59.4,55.1, 37.9. HRMS-CI calcd. for C₁₈H₂₃NO₃ (M+H⁺) 302.1678, found302.1756.

Example 34

Prepared following examle 13, using di(p-anisyl)methyl amine followed byacid cleavage in 78% yield for 2 steps, >99% de and ee. ¹H NMR (250 MHz,CD₃OD) δ 7.25-7.51 (m, 5H), 6.82 (d, 16.0 Hz, 1H), 6.30 (dd, J=16.0 Hz,8.8 Hz, 1H), 4.08 (dd, J=8.8 Hz, 3.4 Hz, 1H), 3.92 (m, 1H), 3.58 (m,2H). ¹³C NMR (63 MHz, CD₃OD) δ 138.7, 129.8, 129.7, 129.2, 127.9, 121.0,72.2, 64.0, 57.4. HRMS-CI calcd. for C₁₁H₁₅NO₂ (M+H⁺) 194.1103, found194.1179.

Example 35

The product was obtained in 67% yield, >99% de. ¹H NMR (250 MHz,acetone-d₆) δ 7.25-7.51 (m, 5H), 5.82 (ddt, J=15.3 Hz, 8.6 Hz, 1.3 Hz,1H), 5.67 (dt, J=15.3 Hz, 5.5 Hz, 1H), 3.96 (dd, J=5.5 Hz, 1.3 Hz, 2H),3.87 (m, 1H), 3.74 (d, J=13.3 Hz, 1H), 3.62 (dd, J=10.6 Hz, 5.5 Hz, 1H),3.51 (dd, J=10.6 Hz, 6.2 Hz, 1H), 3.48 (d, J=13.3 Hz, 1H), 3.29 (s, 3H),3.07 (dd, J=8.6 Hz, 7.5 Hz, 1H), 2.20 (s, 3H). ¹³C NMR (90 MHz, CDCl₃) δ137.9, 134.5, 129.0, 128.6, 127.5, 125.7, 72.3, 69.4, 68.9, 66.5, 59.4,58.2, 38.1. HRMS-CI calcd. for C₁₅H₂₃NO₃ (M+H⁺) 266.1678, found266.1764.

Example 36

Prepared by protection with Boc₂O of the compound in example 34 in 89%yield, >99% de and ee. ¹H NMR (360 MHz, CD₃OD) δ 7.18-7.41 (m, 5H), 6.58(d, J=15.7 Hz, 1H), 6.27 (dd, J=15.7 Hz, 7.1 Hz, 1H), 4.27 (m, 1H), 3.68(m, 1H), 3.58 (m, 2H), 1.45 (s, 9H). ¹³C NMR (90 MHz, CD₃OD) δ 157.8,138.3, 133.1, 129.5, 128.5, 127.5, 127.4, 80.4, 75.2, 64.6, 56.1,28.8.HRMS-CI calcd. for C₁₆H₂₃NO₄ (M+H⁺) 294.1627, found 294.1705.

Example 37

(D)-Ribose (158 mg, 1.05 mmol) was dissolved in EtOH (10 mL) and to thissolution was added N-benzylmethylamine (127 mg, 1.05 mmol), followed by(E)-2-phenylethenyl boronic acid (163 mg, 1.1 mmol). The reaction flaskwas sealed with a plastic stopper and the reaction mixture wasvigorously stirred for 24 hours at ambient temperature. After theremoval of volatiles, the residue was redissolved in dichloromethane andpurified by flash chromatography on silicagel usingdichloromethane-methanol (600:50) as the eluent to obtain 278 mg of pureproduct (74% yield, >99% de). ¹H NMR (360 MHz, CD₃OD) δ 7.20-7.45 (m,10H), 6.61 (d, J=16.0 Hz, 1H), 6.33 (dd, J=16.0 Hz, 9.8 Hz, 1H), 3.98(t, J=8.5 Hz, 1H), 3.65-3.88 (m, 5H), 3.58 (d, J=13.2 Hz, 1H), 3.49 (t,J=8.8 Hz, 1H), 2.25 (s, 3H). ¹³C NMR (90 MHz, CD₃OD) δ 138.9, 138.0,137.8, 130.5, 129.6, 129.5, 128.8, 128.6, 127.6, 124.3, 77.2, 75.4,71.4, 70.8, 64.1, 60.1, 37.9. HRMS-CI calcd. for C₂₁H₂₇NO₄ (M+H⁺)358.1940, found 358.1987.

Example 38

Prepared from (D)-Arabinose as in example 37 in 77% yield, >99% de. ¹HNMR (360 MHz, CD₃OD) δ 7.20-7.43 (m, 15H), 6.34 (d, J=16.2 Hz, 1H), 6.20(dd, J=16.2 Hz, 8.7 Hz, 1H), 4.98 (s, 1H), 3.88 (m, 2H), 3.77 (dd,J=11.4 Hz, 3.1 Hz, 1H), 3.68 (m, 1H), 3.63 (dd, J=11.4 Hz, 5.9 Hz, 1H),3.45 (dd, J=8.7 Hz, 5.8 Hz, 1H). ¹³C NMR (90 MHz, CD₃OD) δ 138.3, 135.0,129.6, 129.4, 128.9, 128.6, 128.4, 128.2, 128.0, 127.5, 73.2, 73.0,72.9, 65.1, 64.7, 63.0. HRMS-CI calcd. for C₂₆H₂₉NO₄ (M+H⁺) 420.2096,found 420.2155.

Example 39

Prepared from (D)-Xylose as in example 37 except that 2-furyl boronicacid was used and the reaction was run for 48 hours in MeOH in 67%yield, >99% de. ¹H NMR (360 MHz, CD₃OD) δ 7.55-7.60 (br, 1H), 7.21-7.38(m, 5H), 6.43 (br, 2 H), 4.27 (m, 1H), 4.05 (m, 1H), 3.50-3.75 (m, 6H),3.15 (m, 1H). ¹³C NMR (90 MHz, CD₃OD) δ 173.0, 145.3, 137.6, 130.6,130.4, 130.0, 128.4, 113.5, 111.9, 72.9, 72.5, 71.6, 64.0, 63.0, 59.9,37.0. HRMS-CI calcd. for C₁₈H₂₃NO₇ (M+H⁺) 366.1474, found 366.1553.

Example 40

(D)-Arabinose (624 mg, 4.16 mmol) was dissolved in EtOH (15 mL) and tothis solution was added 1,1-di-(p-anisyl)methylamine (1,012 mg, 4.16mmol), followed by (E)-2-phenylethenyl boronic acid (670 mg, 4.53 mmol).The reaction flask was sealed with a plastic stopper and the reactionmixture was vigorously stirred for 24 hours at ambient temperature.Volatiles were removed under vacuum and the residue was heated with 80%acetic acid (10 mL) at 80° C. for 1 hour. Upon cooling, the reactionmixture was diluted with water (20 mL) and further acidified with 3 Nhydrochloric acid (10 mL). After the extraction with diethyl ether (3×50mL), water was evaporated and the resulting residue redissolved inmethanol-triethylamine (10:1 by volume, 10 mL). To this solution wasadded di-tert-butyl dicarbonate (2,200 mg, 10 mmol) and the reactionmixture was heated at 45° C. for 40 min. After the removal of volatiles,pure product was isolated by flash column chromatography on silicagelusing dichloromethane-methanol (850:150) as the eluent. Obtained 574 mgof pure product (39% yield for 3 steps, >99% de). ¹H NMR (360 MHz,CD₃OD) δ 7.15-7.42 (m, 5H), 6.57 (d, J=15.9 Hz, 1H), 6.35 (dd, J=15.9Hz, 5.6 Hz, 1H), 4.38 (m, 1H), 3.58-3.81 (m, 5H), 1.45 (S, 9H). ¹³C NMR(90 MHz, CD₃OD) δ 158.3, 138.5, 132.2, 129.5, 129.3, 128.4, 127.4, 80.5,72.7, 72.5, 71.7, 65.0, 56.2, 28.8. HRMS-CI calcd. for C₁₈H₂₇NO₆ (M+H⁺)354.1838, found 354.1876.

Example 41

Prepared similarly to example 40 in 43% overall. ¹H NMR (360 MHz, CD₃OD)δ 7.27 (dd, J=4.7 Hz, 1.0 Hz, 1H), 7.03 (d, 3.7 Hz, 1H), 6.96 (dd, J=4.7Hz, 3.7 Hz, 1H), 5.05 (d, J=8.3 Hz, 1H), 4.07 (d, J=8.3 Hz, 1H),3.58-3.81 (m, 4H), 1.43 (S, 9H). ¹³C NMR (90 MHz, CD₃OD) δ 157.9, 146.0,127.6, 125.8, 125.1, 80.6, 72.8, 72.7, 71.4, 64.9, 54.5, 28.7. HRMS-CIcalcd. for C₁₄H₂₃NO₆S (M+H⁺) 334.1246, found 334.1324.

Example 42

Obtained in 85% yield by ozonolysis of the compound in example 36 inmethanol at −70 C for 5 min with subsequent methylsulfide workup. Thecrude product was purified by flash column chromatography on silicagelusing dichloromethane-methanol (880:120) as the eluent. ¹H NMR (360 MHz,DMSO-d₆) δ 7.15-7.48 (m, 10H), 5.81-6.09 (m, 1H), 4.95 (S, 1H),4.89-5.13 (m, 2H), 4.08-4.18 (m, 1H), 3.77-3.91 (m, 1H), 3.58-3.74 (m,1H), 3.35 (br, 2H), 2.74 (br, 1H). ¹³C NMR (90 MHz, DMSO-d₆) δ 144.8,144.5, 144.3, 144.1, 128.4, 128.3, 128.2, 127.2, 127.0, 126.8, 126.7,101.5, 95.1, 73.2, 72.4, 68.6, 67.4, 65.4, 64.4, 64.0, 60.5. HRMS-CIcalcd. for C₁₇H₁₉NO₃ (M+H⁺) 286.1365, found 286.1450.

Example 43

Obtained in 89% yield by ozonolysis of the compound in example 40, inmethanol at −70° C. for 5 min with subsequent methylsulfide workup. Thecrude product purified by flash column chromatography on silicagel usingdichloromethane-methanol (8:2) as the eluent.

¹³C NMR (90 MHz, DMSO-d₆) δ 155.9, 155.7, 93.3, 93.0, 77.9, 77.5, 77.2,72.7, 72.4, 68.3, 66.8, 66.5, 61.2, 60.9, 55.6, 55.2, 48.6, 28.3.HRMS-CI calcd. for C₁₁H₂₁NO₇ (M+H⁺) 280.1318, found 280.1400

What is claimed:
 1. A process for producing a compound of formula 1comprising:

providing compounds of formula 13 and formula 14

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl,acylalkyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl,diarylalkylsilyl, triarylsilyl, phosphinyl, and —YR, where Y is selectedfrom the group consisting of —O—, —NR_(a)—, —S—, —SO—, and —SO₂—, and Rand R_(a) are each independently selected from the group consisting ofhydrogen, alkyl, aryl, heteroaryl, and acyl, or R¹ and R² together forma bridge of 2 to 20 carbon atoms; and where R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, carboxy,carboxamido, alkyl, cycloalkyl, aryl and heteroaryl, provided that thecompound of formula 14 is not paraformaldehyde; providing a compound offormula 15 or a compound of formula 19

where R⁵ is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl, alkenyl, alkynyl and allenyl; R⁶, R⁷ and R⁸ areselected from the group consisting of hydroxy, alkoxy, aryloxy,heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkyl-amino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form amethylene bridge of 3 to 7 atoms; X is a positive counter ion, and n is0 or 1; mixing said compounds of formula 13, formula 14, and formula 15or 19 to form a reaction mixture; and allowing the reaction mixture toreact to form the compound of formula
 1. 2. The process of claim 1,wherein said reaction mixture further comprises a Lewis acid.
 3. Theprocess of claim 1, wherein R⁶ and R⁷ are each —OR.
 4. The process ofclaim 3, wherein n is 1, R⁸ is F, and said reaction mixture furthercomprises a compound of the formula SiR⁹R¹⁰R¹¹R¹², where R⁹ is selectedfrom the group consisting of halo, alkoxy, acyloxy, triflate,alkylsulfonate and arylsulfonate, and R¹⁰, R¹¹, and R¹² are eachindependently selected from the group consisting of alkyl, cycloalkyl,aryl, alkoxy, aryloxy and chloro.
 5. The process of claim 1, wherein R³is carboxy and the compound of formula 1 is an amino acid.
 6. Theprocess of claim 1, wherein R⁵ is alkenyl.
 7. The process of claim 1,wherein R³ is acylalkyl and the compound of formula 1 is an α-aminocarbonyl compound.
 8. The process of claim 7, wherein R⁵ is alkenyl. 9.The process of claim 1, wherein R³ is selected from the group consistingof aminoalkyl, alkylamino-alkyl, dialkylamino-alkyl, and arylamino-alkyland the compound of formula 1 is a 1,2-diamine.
 10. The process of claim1, wherein R³ is hydroxyalkyl and the compound of formula 1 is an aminoalcohol.
 11. A process for generating a combinatorial library, saidprocess comprising: providing compounds of formula 13 and formula 14

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl,acylalkyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl,diarylalkylsilyl, triarylsilyl, phosphinyl, and —YR, where Y is selectedfrom the group consisting of —O—, —NR_(a)—, —S—, —SO—, and —SO₂—, and Rand R_(a) are each independently selected from the group consisting ofhydrogen, alkyl, aryl, heteroaryl, and acyl, or R¹ and R² together forma bridge of 2 to 20 carbon atoms; and where R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, carboxy,carboxamido, alkyl, cycloalkyl, aryl and heteroaryl provided that thecompound of formula 14 is not paraformaldehyde; providing a compound offormula 15 or a compound of formula

where R⁵ is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl, alkenyl, alkynyl and allenyl; R⁶, R⁷ and R⁸ areselected from the group consisting of hydroxy, alkoxy, aryloxy,heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkyl-amino,dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form amethylene bridge of 3 to 7 atoms; X is a positive counter ion, and n is0 or 1; mixing said compounds of formula 13, formula 14, and formula 15or 19 to form a reaction mixture; and allowing the reaction mixture toreact to form the combinatorial library.
 12. The process of claim 1,wherein: the compounds of formula 13, formula 14 and formula 15 or 19are mixed in a solvent selected from the group consisting of water,methanol, and ethanol, or a mixture thereof.
 13. The process of claim 1,wherein: the compounds of formula 13, formula 14 and formula 15 or 19are mixed in the presence of air.
 14. The process of claim 1, wherein:the compounds of formula 13, formula 14 and formula 15 or 19 are mixedwithout heating.
 15. The process of claim 1, wherein: R³ and R⁴ are notboth hydrogen.
 16. The process of claim 1, wherein: the compounds offormula 13, formula 14, and formula 15 or 19 are mixed to form areaction mixture in a single step.
 17. The process of claim 1, wherein:the compound of formula 13 is an amino carbonyl compound and thecompound of formula 1 is an N-acylalkylamino carbonyl compound.
 18. Theprocess of claim 1, wherein: R³ is hydroxyaryl and the compound offormula 1 is an amino phenol.
 19. The process of claim 2, wherein nis
 1. 20. The process of claim 1, wherein: at least one of the compoundsof formula 13, 14, 15 or 19 is chiral and the compound of formula 1 isproduced stereoselectively.
 21. The process of claim 11, wherein: thecompounds of formula 13, formula 14, and formula 15 or 19 are mixed toform a reaction mixture in a single step.